Project Summary/Abstract A major goal of addiction research is to gain an understanding of the neuroanatomical and molecular changes that underlie the onset and persistence of drug addiction, as well as the pronounced propensity for relapse observed in addicts. One powerful mechanism that may underlie aspects of persistence is epigenetics. Epigenetics (i.e. modulation of gene expression that occurs through altered chromatin structure without fundamental changes to the DNA sequence itself) has been shown to establish stable changes in cell function. These persistent changes in cell function can give rise to significant changes at the synaptic, molecular, and behavioral level. Currently, we still know very little about the epigenetic mechanisms that could establish the persistence characteristic of drug-seeking behavior. One place to begin is to gain an understanding of the epigenetic mechanisms that underlie the association of drugs of abuse with specific cues. As a neuropsychiatric disease, addiction can be partially characterized by the strong association between the contextual cues of drug exposures and the rewarding properties of the drug. These cues have been shown to be strong drivers of drug-seeking behavior, even following year- to decades-long periods of abstinence from drug use. As in long-term memory, the persistence of these drug associations and the consequent drug-seeking behavior involve altered gene expression. The neuron specific nucleosome remodeling nBAF (neuronal Brg1-Associated Factor) complex is an important regulator of transcription required for long-term memory formation and long-lasting forms of synaptic plasticity. A potentially key subunit of the nBAF complex is Calcium-RESponsive Transactivator (CREST). CREST is an exciting subunit to study because it has the ability to integrate cocaine-induced calcium signaling with complex epigenetic machinery to regulate gene expression required for long-term consequences of cocaine action. To date, there is nothing known about the role of CREST in cocaine action. The focus of Aim 1 is to determine the role of CREST in cocaine action. Aim 2 proposes to test the role of CREST in cocaine- induced neuronal plasticity. Finally, in Aim 3, we will explore the mechanism by which CREST affects cocaine-associated memory formation using next-generation sequencing methods (including RNA-seq and ChIP-seq). The results obtained from these experiments will elucidate the role of CREST in cocaine- associated memories. Understanding how CREST contributes to robust drug-associated memories may aid in the development of therapeutic treatments that could be leveraged to help combat substance abuse problems.